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Verzenios ® (abemaciclib)
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What were the most frequent adverse events with Verzenios® (abemaciclib) in early breast cancer in monarchE?
The most common treatment-emergent adverse events in the abemaciclib treatment arm at the AFU1 analysis of monarchE were diarrhea (83.5%), neutropenia (45.8%), and fatigue (40.6%).
monarchE Clinical Trial in Early Breast Cancer Safety Results
The safety profile of abemaciclib in monarchE was consistent with previous MONARCH studies with no new safety concerns.1,2
The most comprehensive safety analysis of the monarchE study data was conducted at the additional follow-up 1 (AFU1) analysis (median follow-up, 27 months; data cutoff date: April 1, 2021) and so those results are described in detail in this response. Safety data from the AFU1 analysis are considered to be mature as the median duration of treatment was 24 months with 90% of patients off the study treatment period.2
Safety findings at the recent overall survival interim analysis (OS IA2) (median follow-up, 42.0 months; data cutoff date: July 1, 2022) with all treated patients off abemaciclib were consistent with previous analyses and are summarized at the end of this response (see Updated Safety Results).3
Abemaciclib: most frequent adverse events in early breast cancer (EBC)
Clinically Relevant Adverse Events in Abemaciclib-Treated Patients in monarchE
Information on the adverse events (AEs) that are considered clinically relevant to abemaciclib are summarized in Clinically Relevant AEs Observed in ≥10% of Patients in Abemaciclib + ET Arm at AFU1 Analysis of monarchE. Data on the ET only arm are included for comparison.2
In monarchE, the most frequent clinically relevant AEs of any grade occurring in ≥10% patients in the abemaciclib arm were diarrhea, infections, neutropenia, fatigue, nausea, anemia, headache, vomiting, stomatitis, thrombocytopenia, decreased appetite, alopecia, increased alanine aminotransferase or aspartate aminotransferase, and rash.2
Grade ≥3 AEs occurred more frequently in patients treated with abemaciclib (49.7% vs 16.3%) and were predominantly laboratory cytopenias without clinical complications.2
|
Abemaciclib + ET (N=2791) |
ET Alone (N=2800) |
||||||
Event Term, % |
Any Grade |
Grade 1 |
Grade 2 |
Grade ≥3 |
Any Grade |
Grade 1 |
Grade 2 |
Grade ≥3 |
Patients with ≥1 AEa |
98.4 |
5.9 |
42.7 |
49.7 |
88.8 |
22.6 |
49.9 |
16.3 |
Diarrhea |
83.5 |
45.0 |
30.7 |
7.8b |
8.6 |
6.6 |
1.9 |
0.2 |
Infectionsc |
51.2 |
8.8 |
36.9 |
5.6 |
39.4 |
8.2 |
28.2 |
3.0d |
Neutropenia |
45.8 |
6.4 |
19.8 |
19.6 |
5.6 |
2.4 |
2.4 |
0.8 |
Fatigue |
40.6 |
22.6 |
15.1 |
2.9 |
17.8 |
13.5 |
4.2 |
0.1 |
Nausea |
29.5 |
22.3 |
6.7 |
0.5 |
9.0 |
7.1 |
1.9 |
0.1 |
Anemia |
24.4 |
13.7 |
8.6 |
2.0 |
3.7 |
2.7 |
0.7 |
0.4 |
Headache |
19.6 |
14.9 |
4.4 |
0.3 |
15.0 |
11.5 |
3.4 |
0.2 |
Vomiting |
17.6 |
13.4 |
3.6 |
0.5 |
4.6 |
3.5 |
1.0 |
0.1 |
Stomatitise |
13.8 |
11.1 |
2.6 |
0.1 |
5.4 |
4.8 |
0.6 |
0.0 |
Thrombocytopenia |
13.4 |
9.9 |
2.2 |
1.3 |
1.9 |
1.4 |
0.3 |
0.1 |
Decreased appetite |
11.8 |
8.7 |
2.5 |
0.6 |
2.4 |
1.9 |
0.5 |
0.1 |
Alopecia |
11.2 |
10.1 |
1.1 |
NA |
2.7 |
2.4 |
0.3 |
0.0 |
ALT increase |
12.3 |
6.6 |
2.9 |
2.8 |
5.6 |
4.0 |
0.9 |
0.7 |
AST increase |
11.8 |
7.9 |
2.1 |
1.9 |
4.9 |
3.7 |
0.7 |
0.5 |
Rash |
11.2 |
8.6 |
2.2 |
0.4 |
4.5 |
3.7 |
0.8 |
0.0 |
Abbreviations: AE = adverse event; AFU1 = additional follow-up 1; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; ET = endocrine therapy; NCI = National Cancer Institute.
aThe severity of AEs were recorded by investigators and graded by the NCI-CTCAE v4.
bNo G4 events, one G5 event.
cInfection is a composite term that includes all reported preferred terms that are part of the infections and infestations system organ class.
dFour G5 events.
eStomatitis is a consolidated term that includes mouth ulceration, mucosal inflammation, oropharyngeal pain, and stomatitis.
Common Treatment-Emergent Adverse Events in monarchE
The most common treatment-emergent adverse events (TEAEs) in the abemaciclib treatment arm at the AFU1 analysis were diarrhea, neutropenia, and fatigue as seen in Most Common TEAEs in the Abemaciclib Arm or ET Alone Arm at the AFU1 Analysis of monarchE. The most common TEAEs in the ET alone arm were arthralgia, hot flush, and fatigue. Other TEAEs are listed in Most Common TEAEs in the Abemaciclib Arm or ET Alone Arm at the AFU1 Analysis of monarchE.4
|
Abemaciclib + ET |
ET Alone |
||||
TEAE, % |
Any Grade |
Grade 3 |
Grade 4 |
Any Grade |
Grade 3 |
Grade 4 |
Diarrhea |
83.5 |
7.8 |
0a |
8.6 |
0.2 |
0 |
Neutropenia |
45.8 |
18.9 |
0.7 |
5.6 |
0.7 |
0.1 |
Fatigue |
40.6 |
2.9 |
NAb |
17.8 |
0.1 |
NAb |
Leukopenia |
37.6 |
11.2 |
0.1 |
6.6 |
0.4 |
NA b |
Abdominal pain |
35.5 |
1.4 |
NAb |
9.8 |
0.3 |
NAb |
Nausea |
29.5 |
0.5 |
NA b |
9.0 |
0.1 |
NAb |
Arthralgia |
26.6 |
0.3 |
NAb |
37.9 |
1.0 |
NAb |
Anemia |
24.4 |
2.0 |
0.0 |
3.7 |
0.3 |
0.0 |
Headache |
19.6 |
0.3 |
NAb |
15.0 |
0.2 |
NAb |
Vomiting |
17.6 |
0.5 |
0 |
4.6 |
0.1 |
0 |
Hot flush |
15.3 |
0.1 |
NAb |
23.0 |
0.4 |
NA b |
Lymphopenia |
14.2 |
5.3 |
0.1 |
3.4 |
0.5 |
0 |
Cough |
14.0 |
0.0 |
NA b |
7.9 |
0 |
NA b |
Thrombocytopenia |
13.4 |
1.0 |
0.3 |
1.9 |
0.1 |
0.1 |
Lymphedema |
12.4 |
0.2 |
NA b |
8.9 |
0.0 |
NA b |
Alanine aminotransferase increase |
12.3 |
2.6 |
0.2 |
5.6 |
0.7 |
0 |
Urinary tract infection |
12.0 |
0.6 |
0 |
7.5 |
0.2 |
0 |
Constipation |
11.9 |
0.1 |
0 |
6.0 |
0.0 |
0 |
Aspartate aminotransferase increased |
11.8 |
1.8 |
0.1 |
4.9 |
0.5 |
0 |
Decreased appetite |
11.8 |
0.6 |
0 |
2.4 |
0.1 |
0 |
Alopecia |
11.2 |
NAc |
NAc |
2.7 |
NAc |
NAc |
Rash |
11.2 |
0.4 |
0 |
4.5 |
0 |
0 |
Blood creatinine increased |
11.1 |
0.1 |
0 |
0.8 |
0 |
0 |
Dizziness |
10.9 |
0.1 |
NAb |
6.7 |
0.0 |
NAb |
Upper respiratory tract infection |
10.8 |
0.2 |
0 |
8.5 |
0 |
0 |
Pain in extremity |
10.2 |
0.1 |
NAb |
11.6 |
0.1 |
NAb |
Back pain |
10.1 |
0.4 |
NAb |
12.4 |
0.3 |
NAb |
Pyrexia |
10.0 |
0.1 |
00 |
4.5 |
0 |
0 |
VTEd PE |
2.5 1.0 |
1.1 0.9 |
0.2 0.1 |
0.6 0.1 |
0.3 0.1 |
0a 0a |
ILDe |
3.2 |
0.4 |
0b |
1.3 |
0.0 |
0 |
Abbreviations: AFU1 = additional follow-up 1; CTCAE = Common Terminology Criteria for Adverse Events; ET = endocrine therapy; ILD = interstitial lung disease; MedDRA = Medical Dictionary for Regulatory Activities; NA = not applicable; PE = pulmonary embolism; SMQ =Standardised MedDRA Queries; TEAE = treatment-emergent adverse event; VTE = venous thromboembolism.
aOne Grade 5 event occurred.
bMax Grade 3 event (according to CTCAE v4).
cMax Grade 2 event (according to CTCAE v4).
dIdentified by selected terms in Embolic and thrombotic events SMQ.
eIdentified by Interstitial lung disease SMQ.
Adverse Events of Interest in monarchE
Adverse events of interest occurring in the abemaciclib + ET arm of monarchE are summarized below:
- Diarrhea was mostly low grade (grade 1/2: 76%); grade 2/3 events were highest in the first month (20.5%), and most were short-lived (≤7 days) and did not recur.
- Neutropenia was the most frequently reported grade ≥3 AE (19.6%), with a median time to onset of 1 month, and was not associated with severe infections.
- Fatigue was predominantly grade 1 (22.6%).
- Grade ≥3 increased transaminases was reported at 3.5% (median time to onset: 3 months) and was managed with a dose hold or reduction and mostly did not recur.
- Increased serum creatinine was the most common laboratory abnormality reported with 99% of patients having a grade 1 or 2 event.
- Most venous thromboembolic events (VTEs) were grade ≥3 and primarily pulmonary embolism (PE) events (1.0%) leading to hospitalization in only 0.7% of those with a PE.
- Increased VTE risk was observed with tamoxifen as the initial ET compared to aromatase inhibitors (4.3% vs 1.8%).
- Most interstitial lung disease events were grade 1 and primarily pneumonitis, with 0.4% experiencing grade ≥3 events and 1 fatal event.
- Any grade alopecia occurred in 11.2% of the abemaciclib-treated patients.
- The safety profile across the age subgroups was generally consistent with the overall safety profile.2,5
Serious Adverse Events and Deaths in monarchE
Serious adverse events occurred more frequently in patients treated with abemaciclib (15.2% vs 8.8%). There were 15 (0.5%) and 10 (0.4%) deaths due to AEs on study treatment or ≤30 days from discontinuation in the abemaciclib + ET arm and ET alone arm, respectively.2
Updated Safety Results
A subsequent analysis (prespecified overall survival interim analysis [OS IA2]) was recently conducted on the monarchE study data. The data cutoff date was July 1, 2022. The median follow-up time for the overall population was 42.0 months, and all patients were off abemaciclib treatment at the time of the analysis. Safety data continue to be consistent with the known safety profile of abemaciclib and with previous analyses (see Safety Findings at OS IA2 Analysis of monarchE). Since the majority of abemaciclib toxicities occurred during the first few months of treatment, at OS IA2 there were minimal changes in the incidence of AEs and no additional discontinuations due to AEs. Thus, the safety findings presented above for AFU1 remain valid.3
No new safety concerns for abemaciclib + ET were identified in the long-term follow-up period, defined as the period beginning >30 days after treatment discontinuation; however, safety monitoring in the long-term follow-up period is ongoing.3
Figure 1 description: At the overall survival interim analysis with a median follow-up of 42.0 months, safety findings were consistent with previous analyses of monarchE.
Abbreviations: AEs = adverse events; ET = endocrine therapy; G1/2/3+ = grade 1/2/3 or worse; ILD = interstitial lung disease; OS IA2 = overall survival interim analysis; PE = pulmonary embolism; VTE = venous thromboembolic event.
monarchE Trial
monarchE is an open-label, randomized, phase 3 trial comparing adjuvant abemaciclib 150 mg twice daily plus endocrine therapy (ET) vs ET alone for a 2-year duration in 5637 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, early breast cancer (EBC) at high risk of recurrence. At the end of the study treatment, patients entered physician-directed ET follow-up for a total of 5-10 years, as clinically indicated. At the preplanned interim analysis in June 2020, this event-driven trial met its primary objective of superior invasive disease-free survival when abemaciclib was combined with ET compared to ET alone.1 The trial is active but not recruiting.7
References
1Johnston SRD, Harbeck N, Hegg R, et al; monarchE Committee Members and Investigators. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. https://doi.org/10.1200/JCO.20.02514
2Rugo HS, O’Shaughnessy J, Boyle F, et al; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study. Ann Oncol. 2022;33(6):616-627. https://doi.org/10.1016/j.annonc.2022.03.006
3Johnston SRD, Toi M, O'Shaughnessy J, et al; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. https://doi.org/10.1016/S1470-2045(22)00694-5
4Harbeck N, Rastogi P, Martin M, et al; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581. https://doi.org/10.1016/j.annonc.2021.09.015
5Data on file, Eli Lilly and Company and/or one of its subsidiaries.
6Johnston SRD, Toi M, O'Shaughnessy J, et al. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes. Cancer Res. 2023;83(5 suppl):GS1-09. American Association for Cancer Research abstract GS1-09. https://doi.org/10.1158/1538-7445.SABCS22-GS1-09
7Endocrine therapy with or without abemaciclib (LY2835219) following surgery in participants with breast cancer (monarchE). ClinicalTrials.gov identifier: NCT03155997. Updated July 14, 2023. Accessed September 5, 2023. https://clinicaltrials.gov/study/NCT03155997
Date of Last Review: 03 February 2023